Background: Medical management with misoprostol for early pregnancy failure has been increasingly used. However, the efficacy, safety and acceptability of this treatment have yet to be established in a large randomized trial. Methods: This multicenter trial randomized 652 women with a first trimester pregnancy failure (anembryonic gestation, fetal demise, incomplete and inevitable spontaneous abortion) to receive either vacuum aspiration (VA, standard of care) or 800 ig vaginal misoprostol in a 1:3 ratio. Subjects receiving misoprostol returned on Day 3. If the expulsion of POC was incomplete, a second dose of 800 ig vaginal misoprostol was given. On Day 8, if the expulsion was still incomplete, VA was offered. On Day 15, all subjects returned for follow-up visit. A telephone interview was conducted on Day 30. Failure was defined as VA (for the misoprostol treatment group) or reaspiration (for the VA group) for any reason within 30 days after the initial treatment. The study was powered to test whether the success rate in the misoprostol group was lower than that in the VA group by 18%. If the difference in success rate between the two groups did not exceed 18%, the treatments would be considered equivalent. Results: Overall, 491 and 161 women, respectively, were randomized to medical or surgical management. Baseline characteristics of the two groups were comparable. In the misoprostol group, 71% of women had complete expulsion by day 3 and 85% by day 8. Overall, treatment failures occurred in 3% of the VA group and 15% of the misoprostol group (difference = 12%, 90% CI 9, 16%). Hemorrhage or endometritis that required hospitalization was rare (< 1%) and there were no differences between the two groups. Emergency hospital visit after the treatment occurred to 3.1% and 2.0% of women who received medical and surgical treatment, respectively (p = 0.59). 78% of women would choose misoprostol again and 83% recommend to others if needed. The acceptability was not different from that in the VA group. Conclusion: Treatment of early pregnancy failure with 800 mg misoprostol per vagina is efficacious and safe with a success rate of around 85%. The risks for hemorrhage and endometritis are very low, and the side-effects are tolerable. It is an acceptable treatment to the majority of the participants.